Cancer-related fatigue (CRF) is a symptom experienced by cancer patients at all stages of disease. CRF is defined as a distressing, persistent, subjective sense of tiredness or exhaustion that is not proportional to recent activity and interferes with usual functioning (Cella et al., J Clin Oncol 19:3385-3391, 2001). Symptom clusters, such as pain, anorexia, nausea, and fatigue, are associated with cancer and its treatment, but fatigue is reported as the most distressing individual symptom (Curt et al., Oncologist 5:353-360, 2000; Vogelzang et al., Semin Hematol 34:4-12, 1997). While therapy for cancer-related pain and emesis is advancing (Cella et al., Oncology 12:369-377, 1998), there is currently insufficient characterization of CRF, resulting in poor management of patients suffering from this condition.
CRF is a complex phenomenon and its pathophysiology likely involves impairment in muscle physiology and central nervous system (CNS) function. Cancer treatments (such as radiation therapy) initiate an acute inflammatory response, increasing the production of interleukin (IL)-1 and tumor necrosis factor (TNF)-α, thereby stimulating the production of IL-6 (Luster et al., Hepatology 19:480-488, 1994), all of which have been associated with alterations in muscle physiology, a contributing factor in fatigue (Natelson and Ponzio, Clin Diagn Lab Immunol 9:747-752, 2002; Fong et al., Am J Physiol Regul Integr Comp Physiol 256:R659-665, 1989). These inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) are thought to circulate to CNS structures (Watkins et al., Life Sci 57:1011-1026, 1995), causing fatigue by altering neurotransmission in the CNS through the afferent vagus nerve root (Dantzer et al., Ann NY Acad Sci 840:586-590, 1998). For example, IL-1 released from activated macrophages is thought to interact with IL-1 receptors in the preoptic nucleus of the hypothalamus (Dinarello, N Engl J Med 317:940-945, 1987). The neurons of the preoptic nucleus that synthesize IL-1 have processes with ramifications to other CNS structures, including the limbic system and the brainstem causing modulation of the neural response leading to significant fatigue (Greenberg et al. J Pain Symptom Management 8:196-200, 1993).
The symptoms of CRF alone can lead to disability, typically reflected as impaired performance in occupational and interpersonal roles. Although advances in cancer treatments continue to lead to higher cure and survival rates, cancer survivors continue to suffer from CRF, presenting significant challenges for health care providers.